1-Benzylpiperazine (BZP; see Molecular structure 1) is one of a small group of benzyl-substituted piperazines, but a much larger group comprises the phenylpiperazines (see Tables 1 and 2). Despite claims by some tablet and capsule suppliers that they are herbal products, piperazine and its derivatives are synthetic substances that do not occur naturally. The large-scale misuse of certain piperazine derivatives (often known as ‘party pills’) started in New Zealand several years ago, but became common in Europe only after 2004. BZP is a central nervous system (CNS) stimulant with around 10 % of the potency of d-amphetamine. Neither BZP nor any other substituted piperazine is listed in the Schedules of the United Nations 1971 Convention on Psychotropic Substances, although several members of this family have been proposed for critical review by WHO in 2009. Following a risk assessment by Europol and the EMCDDA in 2007, a Council Decision of 2008 introduced controls on BZP in the European Union.

One of the phenylpiperazines, 1-(3-chlorophenyl)piperazine (mCPP; see Molecular structure 2), has been even more widespread than BZP. By 2006, it was estimated that almost 10 % of illicit tablets sold in the EU, as part of the illicit ecstasy market, contained mCPP. At the end of 2008 and beginning of 2009, this percentage seems to have increased up to 50% in some Member States. However, because mCPP is used as a starting material for the synthesis of several antidepressant drugs (e.g. trazodone), it could not be subjected to formal risk assessment under the terms of the Council Decision 2005/387/JHA of 2005 on the information exchange, risk assessment and control of new psychoactive substances. Apart from mCPP, the next most commonly-found substituted piperazine was 1-(3-trifluoromethyl-phenyl)piperazine (TFMPP), although it was nearly always seen in combination with BZP. Other mixtures of piperazine derivatives became common during 2008, but most consisted of variations of BZP, TFMPP, mCPP and DBZP, sometimes mixed with other substances such as amphetamine, cocaine, ketamine and MDMA.

Chemistry

Molecular structure 1: 1-benzylpiperazine (BZP)

Molecular formula: C11H16N2Molecular weight: 176.3 g/mold

Molecular structure 2: 1-(3-chlorophenyl)piperazine (mCPP)

Molecular formula: C10H13ClN2Molecular weight: 196.7 g/mol

The substituted piperazines are dibasic amines with no stereoisomers. They are synthetic substances. BZP, normally produced commercially as the dihydrochloride (CAS: 5321-63-1), phosphate or citrate salts, is closely related to the numerous diphenylmethylpiperazines, such as cyclizine (1-diphenyl-methyl-4-methylpiperazine), which have found use as antihistamine/anti-emetic drugs. Other chemical names for mCPP (CAS: free base 6640-24-0) include meta-chlorophenylpiperazine, 1-(3-chlorophenyl)piperazine, 3CPP and 3Cl-PP. These abbreviations should be treated with caution since the term ‘CPP’ is also used for the unrelated herbicide 2-(4-chlorophenoxy)propionic acid.

The piperazine derivatives are not chemically similar to any of the more common substances of misuse, but have a more distant connection with phencyclidine and with 1-phenylethylamine and its derivatives. The suggestion that BZP and other piperazine derivatives are extracted from the pepper plant may arise from confusion with the unrelated substance piperine, a constituent of black pepper (Piper nigrum).

There are two positional isomers of mCPP, namely 1-(4-chlorophenyl)piperazine (also known as pCPP, para-CPP, 4CPP and 4Cl-PP) and 1-(2-chlorophenyl piperazine, (also known as oCPP, ortho-CPP, 2CPP and 2Cl-PP). Both are commercially available. Similar positional isomers occur with the other substituted phenylpiperazines.

Physical form

Piperazine derivatives are usually found in illicit dosage forms as either tablets or capsules, but loose powders also occur. The tablets often carry logos similar to those seen on ‘ecstasy’ tablets. Solutions are encountered less frequently. There are no licensed medicinal products in the EU containing BZP or any of the other substances considered here.

Pharmacology

BZP was created by Burroughs Wellcome as a potential antidepressant drug, but was never developed commercially because it produced similar effects to d-amphetamine, although the relative potency was only 10 %. After a dose of 50–100 mg in human volunteers, BZP was found to increase pulse rate, blood pressure (systolic and diastolic) and pupillary dilation. Following a dose of 150 mg BZP, repeated at 2 hours, the mean blood concentration in human volunteers reached a peak of 600 ng/ml after 6.5 hours.

In a New Zealand Household survey, 2,010 people aged between 13 and 45 years were questioned regarding their use of BZP and related substances. Physical problems reported were (in order of frequency): poor appetite, hot/cold flushes, heavy sweating, stomach pains/nausea, headaches and tremors/shakes. Psychological problems experienced were (in order of frequency): trouble sleeping, loss of energy, strange thoughts, mood swings, confusion and irritability. In both New Zealand and Europe, case reports note an association of BZP with grand mal seizures. There have been a few instances of fatalities involving BZP, but in none was BZP the immediate cause of death, and all of these instances involved other drugs.

Animal studies have demonstrated that BZP stimulates the release and inhibits the reuptake of dopamine, serotonin and noradrenaline. BZP appears to be metabolised by cytochrome P450 (possibly involving the CYP2D6 iso-enzyme) and catechol-O-methyl-transferase (COMT). These systems are prone to genetic polymorphisms, so potential inter-individual differences may occur. In animal and human studies, the main metabolites are 4-hydroxy-BZP, 3-hydroxy-BZP, 4-hydroxy-3-methoxy-BZP, piperazine, benzylamine and N-benzylethylenediamine. The hydroxy-metabolites are also excreted as glucuronic and/or sulphuric acid conjugates in urine.

Following oral administration of mCPP to healthy human male volunteers, the elimination half-life ranges from 2.6 to 6.1 hours with a wide variation in peak blood levels and bioavailability. In rats, mCPP is extensively metabolised by hydroxlation of the aromatic ring and, to a lesser extent, by degradation of the piperazine ring to produce hydroxy-mCPP (two isomers), N-(3-chlorophenyl)ethylenediamine, 3-chloroaniline and hydroxy-3-chloroaniline (two isomers). The hydroxy metabolites are partly excreted as the corresponding glucuronides and/or sulphates, and the chloroanilines are partly excreted as the acetylated derivatives. Physiological and subjective effects reach their peak 1 to 2 hours after oral administration and can last 4 to 8 hours. The negative effects of mCPP, often typical of a serotonin syndrome, include anxiety, dizziness, confusion, shivering, sensitivity to light and noise, fear of losing control, migraine and panic attacks. No fatal poisonings from mCPP have been reported. The subjective effects of mCPP and MDMA are somewhat comparable, but unlike MDMA and BZP, mCPP has little effect on the dopaminergic system.

Synthesis and precursors

BZP has been available from retail chemical suppliers and there have been no reports of illicit synthesis. It can be manufactured by reacting piperazine monohydrochloride with benzyl chloride. The latter precursor is readily available, and piperazine monohydrochloride is easily produced from the commercially-available salts. It is known that 1,4-dibenzylpiperazine (DBZP) can be formed as a side-product in this reaction.

There are several routes to the synthesis of mCPP, the most common of which is the reaction of diethanolamine with m-chloroaniline. Other methods involve the reaction of m-chloroaniline with bis(2-chloroethyl)amine or the reaction of piperazine with m-dichlorobenzene. The other two isomers of CPP could be made in a similar way.It is unlikely that the mCPP found in illicit products has been synthesised in clandestine laboratories since it is available commercially as the base or as the hydrochloride salt.

Mode of use

Other names

Alternative chemical names for BZP include 1-benzyl-1,4-diazacyclohexane, N-benzylpiperazine and, less precisely, benzylpiperazine. Street names have included A2, Legal X and Pep X. In New Zealand, piperazine derivatives were commonly known as ‘party pills’. Like ecstasy, other names may reflect the particular logo on tablets.

Analysis

Analysis of solid samples by gas chromatography and mass spectrometry (GCMS) is straightforward, and derivatisation is not required. Collections of analytical data for BZP and other piperazines have been published. The mass spectrum of BZP has peaks at (m/z) = 91 (base peak), 134, 56, 176 and 65. BZP does not give a colouration with Marquis or Scott’s field tests, but does give a positive reaction with Nitroprusside reagent. There is some cross-reactivity of BZP with commercially available urine immunoassay tests for methamphetamine. BZP reacts with the Syva ‘RapidTest d.a.u.’ for methamphetamine at a concentration of 10 μg/ml, but does not react, even at 100 μg/ml, with the Syva ‘RapidTest d.a.u.’ for amphetamine or the Acon test for methamphetamine. Methods for the identification and quantification of BZP in body fluids usually rely either on GCMS or liquid chromatography coupled with mass spectrometry.

There are no readily-available screening tests for mCPP or the other phenylpiperazine derivatives. In the mass spectrum, the principal ions (m/z) of mCPP are 154 (base peak), 196, 156, 56 and 138. However, mass spectrometry does not distinguish mCPP from its isomers (oCPP and pCPP).

Typical purities

In illicit products, the typical dose of BZP ranges from 50 to 200 mg. In Europe, BZP is often found in combination with other piperazine derivatives (e.g. mCPP, TFMPP, DBZP) and less commonly mixed with other well-known substances such as MDMA, amphetamine, ketamine and caffeine. A study in Belgium conducted by the Scientific Institute of Public Health reported that the amount of mCPP in tablets in 2008 was between 90 and 110 mg for more than 40 % of cases (of 32 samples). For comparison, when used in psychiatry in challenge tests of the serotonin system, the dose of mCPP is typically 50 mg for a 70 kg person.

Control status

Neither BZP nor any other substituted piperazine is listed in the Schedules of the United Nations 1971 Convention on Psychotropic Substances. However, several members of this family have been proposed for critical review by the WHO in 2009. Following a risk assessment in 2007, a Council Decision of 2008 introduced controls on BZP in the European Union.

Prevalence

Prevalence data on BZP and other piperazines is very limited. An online survey conducted in late 2009 in collaboration with the United Kingdom’s dance music magazine Mixmag showed that amongst this particular user group of clubbers 25.8 % had ever tried BZP and 12.1 % had tried it within last year (Winstock, 2010). In 2011, the same survey showed a drop with 17.2 % having ever tried BZP and 5.0 % having tried it within the last year (Mixmag, the 2011 Drugs survey, March edition 2011).

Street price

Medical use

BZP has no current human or veterinary pharmaceutical use in any country. BZP is sometimes erroneously described as a ‘worming agent’. Although piperazine itself is used as an anthelminthic drug, neither BZP nor any other piperazine derivative is licensed for this purpose. As an agonist at the 5HT2C receptor, and an antagonist at the 5HT2B receptor, mCPP has been widely used as a probe of serotonin function in psychiatric research. An industrial use of mCPP is as an intermediate in the production of trazodone and three related substances.Trazodone is licensed in a number of Member States for the treatment of depression and other disorders. The substance 1-(3-chlorophenyl)-4-(3-chloropropyl)-piperazine (mCPCPP) is a precursor used in the manufacture of antidepressant drug nefazodone.

Elliott, S., Smith, C. (2008), ‘Investigation of the first deaths in the United Kingdom involving the detection and quantitation of the piperazines BZP and 3-TFMPP, Journal of Analytical Toxicology, Volume 32, No 2, pp. 172–177.

Staack, R.F., Fritschi, G. and Maurer, H.H. (2002), ‘Studies on the metabolism and toxicological detection of the new designer drug N-benzylpiperazine in urine using gas chromatography-mass spectrometry’, Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences, Volume 773, No 1, pp. 35–46.

Further reading

The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is the reference point on drugs and drug addiction information in Europe. Inaugurated in Lisbon in 1995, it is one of the EU's decentralised agencies. Read more >>